Apparatus and methods for stimulating revascularization and/or tissue growth

ABSTRACT

Apparatus and methods for stimulating revascularization and tissue growth are provided using an apparatus having a directable end region carrying a tissue piercing end effector. The apparatus optionally includes electrodes for depositing RF energy to form a controlled degree of scar tissue formation, means for delivering a controlled amount of a bioactive agent at the treatment site, or both.

REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part application ofcommonly assigned U.S. patent application Ser. No. 08/863,791, now U.S.Pat. No. 5,931,848, Ser. No. 08/863,877, now U.S. Pat. No. 5,910,150,and Ser. No. 08/863,925, now U.S. Pat. No. 5,941,839, all filed May 27,1997.The present application is a continuation-in-part application ofcommonly assigned U.S. patent application Ser. No. 08/863,791, now U.S.Pat. No. 5,931,848, and Ser. No. 08/863,877, now U.S. Pat. No.5,910,150, and Ser. No. 08/863,925, now U.S. Pat. No. 5,941,893, allfiled May 27, 1997, all of which claim the benefit of the filing date ofU.S. provisional patent application Ser. No. 60/032,196, filed Dec. 2,1996.

FIELD OF THE INVENTION

The present invention relates to apparatus and methods for stimulatingrevascularization and tissue growth in an interior region of an organ orvessel, such as the heart. More particularly, the present inventionprovides a device that enables a clinician to stimulate a healingresponse, or deposit a bioactive agent at, a series of sites within ininterior region of an organ or vessel to stimulate revascularization.

BACKGROUND OF THE INVENTION

A leading cause of death in the United States today is coronary arterydisease, in which atherosclerotic plaque causes blockages in thecoronary arteries, resulting in ischemia of the heart (i.e., inadequateblood flow to the myocardium). The disease manifests itself as chestpain or angina. In 1996, approximately 7 million people suffered fromangina in the United States.

Coronary artery bypass grafting (CABG), in which the patient's chest issurgically opened and an obstructed artery replaced with a native arteryharvested elsewhere, has been the conventional treatment for coronaryartery disease for the last thirty years. Such surgery createssignificant trauma to the patient, requires long recuperation times, andcauses a great deal of morbidity and mortality. In addition, experiencehas shown that the graft becomes obstructed with time, requiring furthersurgery.

More recently, catheter-based therapies such as percutaneoustransluminal coronary angioplasty (PTCA) and atherectomy have beendeveloped. In PTCA, a mechanical dilatation device is disposed across anobstruction in the patient's artery and then dilated to compress theplaque lining the artery to restore patency to the vessel. Atherectomyinvolves using an end effector, such as a mechanical cutting device (orlaser) to cut (or ablate) a passage through the blockage. Such methodshave drawbacks, however, ranging from re-blockage of dilated vesselswith angioplasty to catastrophic rupture or dissection of the vesselduring atherectomy. Moreover, these methods may only be used for thatfraction of the patient population where the blockages are few and areeasily accessible. Neither technique is suitable for the treatment ofdiffuse atherosclerosis.

A more recent technique which holds promise for treating a largerpercentage of the patient population, including those patients sufferingfrom diffuse atherosclerosis, is referred to as transmyocardialrevascularization (TMR). In this method, a series of channels are formedin the left ventricular wall of the heart. Typically, between 15 and 30channels about 1 mm in diameter and up to 3.0 cm deep are formed with alaser in the wall of the left ventricle to perfuse the heart muscle withblood coming directly from the inside of the left ventricle, rather thantraveling through the coronary arteries. Some researchers believe thatthe resulting channels improve perfusion of the myocardium withoxygenated blood. Apparatus and methods have been proposed to createsuch channels both percutaneously and intraoperatively (i e., with thechest opened).

U.S. Pat. No. 5,389,096 to Aita et al. describes a catheter-based laserapparatus for use in percutaneously forming channels extending from theendocardium into the myocardium. The catheter includes a plurality ofcontrol lines for directing the tip of the catheter. As the laserablates the tissue during the channel forming process, the surroundingtissue necroses, resulting in fibroid scar tissue surrounding thechannels. U.S. Pat. No. 5,380,316 to Aita et al. describes anintraoperative laser-based system for performing TMR.

U.S. Pat. No. 5,591,159 to Taheri describes mechanical apparatus forperforming TMR comprising a catheter having an end effector formed froma plurality of spring-loaded needles. The catheter first is positionedpercutaneously Within the left ventricle. A plunger is then released sothat the needles are thrust into the endocardium. The needles core outsmall channels that extend into the myocardium as they are withdrawn.The patent suggests that the needles may he withdrawn and advancedrepetitively at different locations under fluoroscopic guidance. Thepatent does not appear to address how tissue is ejected from the needlesbetween the tissue-cutting steps

Although it is generally agreed that TMR benefits many patients,researchers do not agree upon the precise mechanism by which TMRprovides therapeutic benefits. One theory proposes that TMR channelsremain patent for long periods of time, and provide a path by whichoxygenated blood perfuses the myocardium. However, relatively recenthistological studies indicate that TMR channels may close within a shorttime following the procedure. For example, Fleischer et al., in“One-Month Histologic Response Of Transmyocardial Laser Channels WithMolecular Intervention,” Ann. Soc. Thoracic Surg., 62:1051-58 (1996),evaluated histologic changes associated with laser TMR in a 1-monthnonischemic porcine model, and was unable to demonstrate channel patency28 days after TMR.

Other researchers have observed that in laser-based TMR patients, thereappears to he enhanced vascularization of the tissue on the margins ofthe scar tissue resulting from the laser channel-forming process. It hastherefore been hypothesized that the act of causing trauma to portionsof the myocardium may invoke a regenerative process, that enhances thedevelopment of neovascularization and endothelialization in the tissue.

To investigate these alternative theories, researchers have studied theuse of gene therapy in promoting blood vessel growth in the tissuesurrounding laser TMR channels. In one study, researchersintraoperatively administered a single dose of vascular endothelialgrowth factor (VEGF) at the time of laser TMR. Although the study showedno significant increase in myocardial vascularity, the researchershypothesized that a longer duration of VEGF residence may be necessaryto stimulate angiogenesis.

In view of the foregoing, it would be desirable to provide apparatus andmethods for stimulating revascularization and tissue growth in aninterior region of an organ or vessel, such as the heart, by stimulatingnative revascularization and tissue growth mechanisms.

It would also be desirable to provide apparatus and methods forstimulating revascularization and tissue growth by controlling theplacement and size of tissue treatment sites, thereby resulting in acontrolled degree of scar tissue formation.

It would be still further desirable to provide apparatus and methods forstimulating revascularization and tissue growth by depositing acontrolled amount of a bioactive agent, such as an angiogenic growthfactor, at the treatment sites.

SUMMARY OF THE INVENTION

In view of the foregoing, it is an object of this invention to provideapparatus and methods for stimulating revascularization and tissuegrowth in an interior region of an organ or vessel, such as the heart,by stimulating native revascularization and tissue growth mechanisms.

It is another object of the present invention to provide apparatus andmethods for stimulating revascularization and tissue growth bycontrolling the placement and size of tissue treatment sites, therebyresulting in a controlled degree of scar tissue formation.

It is a still further object of this invention to provide apparatus andmethods for stimulating revascularization and tissue growth bydepositing a controlled amount of a bioactive agent, such as a drug oran angiogenic growth factor, at the treatment sites.

These and other objects of the present invention are accomplished byproviding apparatus having a directable end region carrying an endeffector that induces trauma at a treatment site to stimulaterevascularization. The apparatus may optionally include electrodes fordepositing RF energy to form a controlled degree of scar tissueformation, means for depositing a controlled amount of a bioactive agentat the treatment site, or both.

Apparatus constructed in accordance with the present invention comprisesa catheter having a longitudinal axis, an end region that is deflectablerelative to the longitudinal axis, and a tissue piercing end effector.The end effector may optionally include an RF electrode for causing acontrolled degree of necrosis at a treatment site, the capability todeposit a controlled amount of a bioactive agent at the treatment site,or both.

Methods of using the apparatus of the present invention to stimulaterevascularization and/or tissue growth are also provided.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features of the invention, its nature and various advantageswill be more apparent from the accompanying drawings and the followingdetailed description of the preferred embodiments, in which:

FIG. 1 is a view of an illustrative embodiment of apparatus constructedin accordance with the present invention;

FIG. 2 is a perspective view of an end region and end effector of theapparatus of FIG. 1;

FIG. 3 is schematic view of an illustrative arrangement for driving theend effector of FIG. 1;

FIG. 4 is a partial side view of the end effector of the apparatus ofFIG. 1;

FIG. 5 is a schematic view of an alternative illustrative arrangementfor driving an end effector adapted to deliver a bioactive agent,

FIG. 6 is a partial side view of the end effector of the apparatus ofFIG. 5;

FIGS. 7A to 7C are views illustrating operation of the apparatus of FIG.1,

FIG. 8 is a schematic view of another alternative arrangement fordriving the end effector of the apparatus of FIG. 1;

FIG. 9 is a schematic view of a yet another further alternativearrangement for driving an end effector constructed in accordance withthe present invention;

FIGS. 10A and 10B are, respectively, partial side sectional viewsillustrating operation of another end effector of the present invention;

FIGS. 11A and 11B are, respectively, a partial side sectional view andcross-sectional view of a further alternative embodiment of an endeffector of the present invention; and

FIGS. 12A to 12D are views illustrating operation of the end effector ofFIGS. 11 to deposit a pellet of a bioactive agent at a treatment site.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates generally to apparatus and methods fortreating a plurality of tissue sites within a vessel or organ tostimulate tissue growth and revascularization. The apparatus of thepresent invention comprises a catheter having an end region that may beselectively articulated to a position at an angle relative to thelongitudinal axis of the catheter, including a position substantiallyorthogonal to the longitudinal axis.

The end region carries a tissue piercing end effector to induce traumato stimulate native tissue repair and revascularization mechanisms. Theend effector may optionally include an RF electrode to cause acontrolled degree of necrosis, means for depositing a controlled amountof a bioactive agent at the treatment site, or both. The deflectable endregion of the catheter provides precise control over the location of theend region, and thus, the end effector.

Referring to FIG. 1, illustrative apparatus 20 constructed in accordancewith the present invention is described. Apparatus 20 comprises catheter21 having deflectable end region 22, end effector 23 and handle 24,cable 25 and controller 26. Apparatus 20 is coupled via cable 25 tocontroller 26. End effector 23, described in greater detail hereinbelow,pierces myocardial tissue, with or without coring, to attain a treatmentgoal.

End region 22 includes one or more control wires 27 disposed for slidingmovement within catheter 21, such as described in U.S. Pat. Nos.5,389,073 and 5,330,466 to Imran, which are incorporated herein byreference. Application of a predetermined proximal force on control wire27 (indicated by arrow A), deflects end region 23 a predetermined amount(shown in dotted lines in FIG. 2). Accordingly, end region 23 may bemoved between a transit position, parallel to longitudinal axis 28 ofcatheter 21 and a working position (as shown) substantially orthogonalto longitudinal axis 28.

In a preferred embodiment, wherein the end effector comprises a flexiblewire having a sharpened tip, controller 26 includes a hydraulic orpneumatic piston, valve assembly and control logic for extending andretracting the end effector beyond the distal endface of end region 23responsive to commands input at handle assembly 24 or a footpedal (notshown) Controller 26 optionally may further contain RF generatorcircuitry for energizing electrodes disposed on the end effector tocause a controlled degree of necrosis at the treatment site.Alternatively, or in addition, controller 26 may include a source of abioactive agent, and means for delivering controlled amounts of thebioactive agent to the treatment site.

Referring now to FIG. 3, end effector 23 and controller 26 of a firstembodiment are described. In FIG. 4, most of catheter 21 and handle 24have been omitted for clarity. End effector 23 comprises tissue piercingcone 41 having optional first and second RF electrodes 42a and 42b,respectively. End effector preferably comprises a rigid material thatretains a sharp tip, such as stainless steel Drive shaft 43, whichextends through cable 25 of FIG. 1, is coupled to end effector 23 viaflexible coupling 44 at its distal end, and to piston 45 at its proximalend. Drive shaft 43 is disposed for reciprocation in end region 22responsive to movement of piston 45. Drive shaft 43 may comprise asingle or braided plastic or metal alloy wire, while flexible coupling44 comprises a sturdy but flexible plastic or metal alloy.

Piston 45 is enclosed within cylinder 46 for proximal and distalmovement. High pressure source 47 is connected to valve 48 and pressurelines 49a and 49b; low pressure source 50 is connected to valve 51 andpressure lines 52a and 52b. Pressure lines 49a and 52a communicate withproximal volume 53a of cylinder 46, whereas pressure lines 49b and 52bcommunicate with distal volume 53b of cylinder 46. Valves 48 and 51 aresynchronized so that when high pressure source 47 is coupled to pressureline 49a (but not 49b), low pressure source 50 is coupled to line 52b(but not 52a), thus driving piston 45 in the distal direction.

Likewise, when valve 48 couples high pressure source 47 to pressure line49b (but not 49a), and valve 51 couples low pressure source 50 to line52a (but not 52b), piston 45 is driven in the proximal direction. Valves48 and 51 are coupled by wiring (not shown) to control logic 54, whichactuates the valves responsive to control commands received from handleassembly 26 or a footpedal (not shown). Cylinder 46 may employ anysuitable medium for moving piston 45, and may be either pneumatic orhydraulic.

Controller 26 optionally includes RF generator circuitry 55 whichgenerates a high frequency (e.g., greater than 100 MHZ) voltage signal.RF generator circuitry 55 is coupled via suitable bushings andconductors (not shown) to electrodes 42a and 42b. Electrodes 42a and 42bmay be arranged to conduct current through tissue located in contactthem, in a bipolar mode, or may conduct current through the tissue andto a ground plate (not shown) in a monopolar mode. In embodiments ofcontroller 26 where RF generator circuitry 55 is provided, control logic54 may be programmed to energize electrodes 42a and 42b when piston 45has attained its maximum distal stroke. Control logic 54 may energizeelectrodes 42a and 42b for a user selected interval to provide acontrolled degree of necrosis in the tissue surrounding the treatmentsite created by end effector 23.

Referring now also to FIG. 6 3, when piston 45 is driven in the distaldirection, end effector 23 extends beyond the distal endface of catheter21 and pierces and extends into tissue T. End effector 23 therebyinduces trauma to tissue T in the form of needle track N. If electrodes42a and 42b and RF generator circuitry 55 are provided, control logic 55may energize the electrodes to cause necrosis of tissue T in a region Rsurrounding the end effector. Control logic 54 then reverses theorientation of valves 48 and 51, thus causing end effector 23 to beretracted from tissue T and into end region 22.

Applicants expect that the trauma caused by needle track N willstimulate naturally occurring mechanisms to repair the wound at thetreatment site. It is further expected that by generating a matrix oftreatment sites, a network of small vessels may become established inthe tissue as it heals. In addition, by providing a controlled degree ofnecrosis, a preselected degree of scar tissue may be induced, thusmimicking the conditions observed to induce revascularization at themargins of laser-formed TMR channels.

With respect to FIGS. 5 and 6, an alternative embodiment of the endeffector and controller of the present invention is described. Onceagain, catheter 21 (except for end region 22) and handle 24 have beenomitted from FIG. 5 for clarity End effector 60 comprises non-coringtissue piercing cone 61 affixed to drive shaft 62. Drive shaft 62includes lumen 63, and extends through cable 25 of FIG. 1 Drive shaft 62is coupled to piston 64 at its proximal end, and is disposed forreciprocation in the guide tube (not shown) responsive to movement ofpiston 64. Drive shaft 62 preferably comprises a thin-walled butflexible plastic or metal alloy tube. End effector 60 may optionallyinclude electrodes 65a and 65b for applying an RF voltage potential tothe tissue to cause a controlled degree of necrosis, as describedhereinabove with respect to the embodiment of FIGS. 3 and 4.

Piston 64 is enclosed within a cylinder in controller 66 for proximaland distal movement. High pressure source 67 is connected to valve 68and pressure lines 69a and 69b; low pressure source 70 is connected tovalve 71 and pressure lines 72a and 72b. Pressure lines 69a and 72acommunicate with proximal volume 73a of the cylinder, whereas pressurelines 69b and 72b communicate with distal volume 73b of the cylinderValves 68 and 71 are synchronized as described hereinabove with respectto like components of FIG. 4, so as to extend and retract end effector60 under the control of control logic 74 responsive to control commandsreceived from handle assembly 26.

Drive shaft 62 includes a plurality of outlet ports 75 located adjacentto cone 61 and a plurality of inlet ports 76 disposed in chamber 77.Chamber 77 contains bioactive agent 80 suspended in a biocompatible highviscosity liquid or paste, and is selectively pressurized by pressuresource 78. Bioactive agent 80, may comprise a drug or an angiogenicgrowth factor, for example, vascular endothelial growth factor (VEGF),fibroblast growth factor, type I (FGF-I) or type II (FGF-II), a genevector, cardio myocytes, or other suitable agent for stimulating tissuegrowth and/or revascularization.

Inlet ports 76 and outlet ports 75 communicate with lumen 63. Inaccordance with one aspect of the present invention, when high pressuresource 78 is actuated to pressurize chamber 77, a controlled amount ofbioactive agent 80 is injected into inlet ports 76 of lumen 63. This inturn causes an equal amount of bioactive agent 80 to be expelled throughoutlet ports 75 of end effector 60 into the adjacent tissue. Controllogic 74 preferably is programmed to actuate high pressure source 78when piston 64 has attained its maximum distal stroke. Controller 66 mayin addition include an RF generator circuitry similar to RF generatorcircuitry 55 of the embodiment of FIG. 3 for energizing electrodes 65aand 65b.

With respect to FIG. 6, when piston 64 is driven in the distaldirection, end effector 60 extends beyond the distal endface of thecatheter and pierces and extends into tissue T. End effector 60 therebycauses trauma to tissue T in the form of needle track N. Once endeffector 60 reaches its maximum depth, control logic 74 actuates highpressure source 78, causing a controlled amount of bioactive agent 80 tobe expelled through outlet ports 75 into the tissue.

If the bioactive agent exits the ports with sufficiently high velocity,it is expected that the bioactive agent will form pockets 81 in thetissue. Alternatively, if the bioactive agent exits outlet ports 75 atlower velocity, it is expected that the bioactive agent will form alayer that coats the interior surface of needle track N. Once thebioactive agent has been deposited, control logic 74 reverses theorientation of valves 68 and 71, thus causing end effector 60 to beretracted from tissue T and into the end region of the catheter. Ifprovided, RF electrodes 65a and 65b may be activated to cauterize tissuein the vicinity of needle track N.

As described hereinabove, applicants expect that the trauma caused byneedle track N will stimulate the release of naturally tissueregenerative mechanisms to repair the wound at the treatment site.Moreover, the introduction of bioactive agent 80 along needle track N isexpected to further stimulate revascularization By generating a matrixof treatment sites within which a bioactive agent has been deposited, itmay be possible to promote the development of a network of small vesselsthat will perfuse the tissue.

Referring now to FIGS. 7A–7C, operation of apparatus 20 in the contextof treating a series of treatment sites to stimulate revascularizationin left ventricular myocardium is described. In FIG. 7A, end region 22of apparatus 20 is shown positioned in a patient's left ventricularcavity, using techniques which are per se known. Specifically, endregion 22 of apparatus 20 is inserted via a femoral artery, and ismaneuvered under fluoroscopic guidance in a retrograde manner up throughthe descending aorta, through aortic arch 201, and down throughascending aorta 202 and aortic valve 203 into left ventricle 204. Aswill of course be understood, insertion of apparatus 20 into the leftventricle is with end region 22 in its transit position.

Previously known imaging techniques, such as ultrasound, MRI scan, CTscan, or fluoroscopy, may be used to verify the location of the endregion 22 within the heart. Alternatively, means may be provided in endregion 22 for emitting an ultrasonic signal which is detectable using anultrasound imaging system outside of the patient. For example, apiezo-electric transducer may be affixed to the tip of the catheter andtuned to a frequency of a color Doppler ultrasound imaging system so asto appear as a bright orange or yellow spot on the display of theultrasound system. Yet another way to detect the location of end region22 is by pinpointing the delay time of an EKG signal at the point ofdetection, using an electrode disposed in end region 22. By looking atthe morphology as well as the temporal characteristics of the EKGsignal, the vertical position of the catheter within the heart chambermay be determined.

Referring to FIG. 7B, once end region is located adjacent a desiredportion of the endocardial surface, end region 22 is deflected to itsworking position, for example, by operating control wire 27. In thismanner end effector 23 is disposed against a surface of the endocardiumto be treated.

Controller 26 is then actuated to cause end effector 23 to pierce andextend into the interior of left ventricular wall 206. When the endeffector reaches its maximum depth, a burst of RF energy may be applied,if desired, to necrose a depth of tissue, an amount of a bioactive agentmay be deposited at the treatment site, or both. Controller 26 thenwithdraws end effector 23 from the tissue.

As shown in FIG. 7C, a series of vertically aligned spaced-apart needletracks 207 may he formed in left ventricular wall 206 by repositioningend region 22 using control wire 27. End effector 23 is then advanced toform a further needle track 207 in the tissue.

The foregoing methods enable a matrix of channels to be formedillustratively in the left ventricular wall. It will of course beunderstood that the same steps may be performed in mirror image toproduce a series of needle tracks in the septal region. It is believedthat the needle tracks may have a beneficial effect if formed anywhereon the walls of the heart chamber, including the septum, apex and leftventricular wall; the above-described apparatus provides this capability

In addition, a stabilization assembly may be employed, for example, asdescribed in copending, commonly assigned U.S. patent application Ser.No. 08/863,877, filed May 27, 1997, to counteract any reaction forcesgenerated by operation of end effector 23.

In FIG. 8, an alternative arrangement for driving the end effector ofthe present invention is described. In controller 130 of FIG. 8, thepiston and cylinder of controller 26 of FIG. 1 are replaced with amechanical drive system. As in FIGS. 3 and 4, most of the catheter andhandle have been omitted for clarity. End effector 131 comprisesnon-coring sharpened tip 132 coupled to drive shaft 133. Drive shaft 133is coupled at its proximal end to push rod 134. Push rod 134 is biasedagainst eccentric cam 135 by spring 136. Cam 135 is mounted on motor137, which rotates cam 135 through one revolution responsive to commandsfrom control logic 138. Control logic 138, in turn, actuates motor 137responsive to commands received, for example, by a button on handle 24(see FIG. 1). Thus, controller 130 extends and retracts end effector 131to create a needle track in the tissue.

As will of course be apparent to one of skill in designingcatheter-based systems, controller 130 may optionally include either theRF generator circuitry and electrodes of the embodiment of FIG. 3, thebioactive agent delivery system described with respect to the embodimentof FIG. 5, or both. As will be further apparent, the specific drivearrangements described hereinabove are intended to be illustrative, andother mechanisms may be readily employed. For example, the specificconfiguration of the pressure sources, pressure lines and the valves inFIGS. 3 and 5 are intended to be merely illustrative. Equivalentmechanisms for extending and retracting the end effector may be readilyemployed within the scope of the present invention. Thus, for example,the end effector may be spring loaded so as to be biased in the extendedposition and reset after having been extended to form each needle track.

Referring now to FIGS. 9, 10A and 10B, a further alternative embodimentof a drive system and end effector suitable for use in the presentinvention are described. In apparatus 140 of FIG. 9, it is again to beunderstood that the handle and most of the catheter have been omittedfor clarity In apparatus 140, a manual drive arrangement has beensubstituted for the controller of the previously described embodiments.In particular, end effector 142 comprises tip 143 having aperture 144coupled to the distal end of drive shaft 145. Proximal end 146 of driveshaft 145 includes actuator ring 147, and proximal end 148 of catheter141 includes rings 149. As will be apparent, drive shaft 144 may bedriven in the distal direction to extend end effector 142 by squeezingactuator ring 147 towards rings 149.

With respect to FIG. 10A, drive shaft 145 includes lumen 150 and pushwire 151 disposed within lumen 150. Push wire 151 terminates at itsproximal end in a plurality of fine wires 152. Wires 152 may comprise,for example, nickel-titanium, and are constructed so that when theyextend through aperture 144, the wires diverge (see FIG. 10B). Push wire151 extends through lumen 150 of drive shaft 145 and terminates inbutton 153. By gripping flange 154 provided on proximal end 146 of driveshaft 145, button 153 may be depressed toward flange 154, therebyextending wires 152 through aperture 144.

FIG. 10A shows end effector 142 extended to pierce and extend intotissue T to form needle track N, for example, by squeezing actuator ring147 towards ring 149. As will of course be understood, this step occursafter the catheter has been disposed within an organ or vessel asdescribed above with respect to FIGS. 7A and 7B. FIG. 10B illustratesthat extension and retraction of wires 152 generates a matrix ofadditional needle tracks N′ Applicant expects that, like the applicationof RF energy to form a controlled layer of scar tissue, or thedeposition of an amount of a bioactive agent, the matrix of needletracks N′ will further stimulate revascularization in the tissue

With respect to FIGS. 11A and 11B, an alternative embodiment of an endeffector is described for depositing a bioactive agent in a pelletizedform. In FIGS. 11, it is to be understood that the handle assembly andmost of the catheter have been omitted. End effector 160 comprises tube161 including beveled non-coring tip 162 mounted in distal end 163 ofcatheter 164. Push rod 165 is disposed for reciprocation in lumen 166 oftube 161. As shown in FIG. 11B, catheter 164 includes lumen 167 in whichtube 161 is disposed, and lumen 168 through which bioactive pellets 170,illustratively, spherical beads, are advanced to end effector 160. Lumen168 includes passageway 169 through which a pellet passes to engage pushrod 165 for delivery.

In accordance with one aspect of the present invention, pellets 170comprise a bioactive agent, as described hereinabove, disposed in abiodegradable binder, such as polycaprolactone or polylactic acid.Pellets 170 are sized to advance through lumen 168 freely and withoutbunching, so that when posh rod is retracted in the proximal directionpast the proximal edge of passageway 169, a single pellet 170 passesinto lumen 166 of tube 161. While pellets 170 are illustrativespherical, it is to be understood that the bioactive agent may bereadily formed into any of a number of other shapes, such as rods,cones, granules, etc., and that the above-described delivery system maybe readily adapted to such other pelletized forms.

Referring now to FIGS. 12A to 12D, operation of the apparatus of FIGS.11 is described. Apparatus including end effector 160 first is disposedwithin an internal organ, such as the left ventricle, as describedhereinabove with respect to FIGS. 7A to 7C. End effector 160 then isoriented so as to be positioned at a desired angle, e.g. perpendicular,to tissue T to be treated. While end effector 160 is being maneuveredinto position, posh rod 165 is extended so that distal endface 171extends past the distal edge of passageway 169, thereby confiningpellets 170 within lumen 168. End effector 160 is urged in the distaldirection to form needle track N, and so that tip 162 penetrates tissueT until catheter 164 abuts against the endocardium (shown in FIG. 12A).

Push rod 165 then is retracted in the proximal direction, so that distalendface 171 is positioned proximally of the proximal edge of passageway169. This in turn permits a single pellet 170 to advance throughpassageway 169 into lumen 166, as shown in FIG. 12B. Because pellets 170are preferably only slightly smaller than the diameter of lumen 166,when a single pellet 170 has advanced into lumen 166, it will blockother pellets from passing through passageway 169 into lumen 166.Alternatively, pellets 170 may be sized so that a predetermined numberof pellets pass into lumen 166 each time push rod 165 is retractedproximally.

Push rod 165 then is driven in the distal direction, urging pellet 170to the end of needle track N, as illustrated in FIG. 12C If RFelectrodes are provided on tip 162, such electrodes may be energized tonecrose a predetermined thickness of tissue in the vicinity of tip 162.End effector 160 then is withdrawn, leaving pellet 170 within needletrack N in tissue T. As described hereinabove, pellet 170 preferablycomprises a biodegradable substance that elutes a suitable bioactiveagent into the tissue surrounding the pellet over a preselected periodof time. It is expected that by depositing a bioactive substance withintissue T, tissue revascularization and growth may be stimulated, asdescribed hereinabove. End effector 160 then is moved to anotherlocation and the foregoing process repeated to seed a plurality ofpellets 170.

While preferred illustrative embodiments of the invention are describedabove, it will he apparent to one skilled in the art that variouschanges and modifications may be made therein without departing from theinvention, and the appended claims are intended to cover all suchchanges and modifications that fall within the true spirit and scope ofthe invention.

1. Apparatus for treating an interior region of a cardiac chamber, theapparatus comprising: a catheter configured for insertion into a cardiacchamber, the catheter having a deflectable end region; an end effectordisposed within distal to the delectable end region, the end effectoradapted to form a needle track at a treatment site in an interior regionof the cardiac chamber, the end effector movable between a firstposition, wherein the end effector is retracted within the end region,and a second position, wherein the end effector is extended beyond adistal endface of the catheter; and means for moving the end regionbetween the first and second positions, wherein the end effector furthercomprises means for depositing a controlled amount of a bioactive agentat the treatment site and wherein the catheter has a plurality oflumens, one of which contains the bioactive agent and wherein thecatheter has a conductor extending from a proximal end of the catheterto an electrode which is distal to the deflectable end region.
 2. Theapparatus of claim 1 wherein the end effector comprises a non-coringsharpened tip.
 3. The apparatus of claim 1 wherein the end effectorfurther comprises an electrode adapted to deliver RF energy to thetreatment site.
 4. The apparatus of claim 1 wherein the end effectorfurther comprises a plurality of fine wires, the fine wires movablebetween a retracted position and an extended position, the plurality offine wires forming a matrix of additional needle tracks at the treatmentsite when extended.
 5. The apparatus of claim 1 wherein the end effectoris coupled to a drive shaft, the apparatus further comprising acontroller including a hydraulic mechanism coupled to the drive shaft toextend and retract the end effector.
 6. The apparatus as defined inclaim 1 wherein the end effector is coupled to a drive shaft, theapparatus further comprising a controller including a pneumaticmechanism coupled to the drive shaft to extend and retract the endeffector.
 7. The apparatus as defined in claim 1 wherein the endeffector is coupled to a drive shaft, the apparatus further comprising amanually actuated mechanism coupled to the drive shaft to extend andretract the end effector.
 8. Apparatus for treating an interior regionof a cardiac chamber, the apparatus comprising: a catheter having adeflectable end region; an end effector adapted to form a needle trackat a treatment site in an interior region of the cardiac chamber, theend effector movable between a first position, wherein the end effectoris retracted within the end region, and a second position, wherein theend effector is extended beyond a distal endface of the catheter; andmeans for depositing a bioactive agent in the needle track when the endeffector is in the second position and wherein the catheter has aplurality of lumens, one of which contains the bioactive agent andwherein the catheter has a conductor extending from a proximal end ofthe catheter to an electrode which is distal to the deflectable endregion.
 9. The apparatus of claim 8 wherein the end effector comprises anon-curing sharpened tip.
 10. The apparatus of claim 8 wherein the endeffector further comprises an electrode adapted to deliver RF energy tothe treatment site.
 11. The apparatus of claim 10 wherein the bioactiveagent is a fluid and the means for depositing comprises supplies thefluid to the end effector under pressure.
 12. The apparatus of claim 8wherein bioactive agent has a pellet form and the means for depositingthe bioactive agent comprises a push rod.
 13. A method of treating aninterior region of a cardiac chamber the method comprising: providingapparatus having a catheter adapted for insertion into a cardiacchamber, the catheter having a deflectable end region including an endeffector adapted to form a needle track at a treatment site in aninterior region of the cardiac chamber, wherein the catheter has aplurality of lumens, one of which contains a bioactive agent, whereinthe catheter has a conductor extending from the proximal end of thecatheter to the distal end of the catheter and the conductor is coupledto the end effector; inserting the apparatus within a cardiac chamber;deflecting the end region to dispose the end effector at a selectedorientation relative to an endocardial surface; actuating the endeffector to form a needle track in an interior region of the cardiacchamber at a treatment site; and delivering a controlled amount of a thebioactive agent at the treatment site, wherein the needle track, afterthe delivering, is substantially closed onto the bioactive agent. 14.The method of claim 13 further comprising delivering RF energy to thetreatment site to create a controlled depth of necrosis at the treatmentsite.
 15. The method of claim 13 wherein delivering a controlled amountof a bioactive agent at the treatment site further comprises injectingthe bioactive agent under pressure sufficient to form a pocket ofbioactive agent in the tissue.
 16. The method of claim 13 whereindelivering a controlled amount of a bioactive agent at the treatmentsite further comprises injecting a pellet comprising a bioactive agent.17. The method as defined in claim 13 wherein the end effector furthercomprises a plurality of fine wires, the fine wires movable between aretracted position and an extended position, the method furthercomprising extending the plurality of fine wires to form a matrix ofadditional needle tracks at the treatment site.
 18. The method asdefined in claim 13 further comprising, following delivering acontrolled amount of a bioactive agent at the treatment site:translating the end region to relocate the end effector; and repeatingactuation of the end effector.
 19. An apparatus, comprising: a catheterconfigured for percutaneous insertion into a cardiac tissue, thecatheter having a proximal region, a steerable distal region, and alumen extending from the proximal region to the steerable distal region;a needle disposed distal to the steerable distal region and movablebetween a first position, wherein the needle is retracted within thedistal region, and a second position, wherein the needle is extendedbeyond the distal region; and a controller coupled near the proximalregion and having a source of a bioactive agent, wherein the controllermechanically measures a controlled amount of the bioactive agent, andwherein the bioactive agent is passed through the lumen, in fluidcommunication with the needle, for delivery into the cardiac tissue,wherein the needle further comprises a means for depositing thecontrolled amount of the bioactive agent into the cardiac tissue, andwherein the catheter has a plurality of lumens, one of which containsthe bioactive agent and wherein the catheter has a conductor extendingfrom a proximal end of the catheter to an electrode which is distal tothe steerable distal region.
 20. The apparatus of claim 19, wherein thebioactive agent has a pellet form.
 21. The apparatus of claim 19,wherein the bioactive agent has a fluid form.
 22. The apparatus of claim19, wherein the controller releases a plurality of discrete units of thebioactive agent through the lumen of the needle.
 23. The apparatus ofclaim 22, wherein the plurality of discrete units of the bioactive agentcomprises a predetermined amount of the bioactive agent.
 24. Theapparatus of claim 19, wherein the needle further comprises an electrodeadapted to delivery RF energy to the cardiac tissue.
 25. The apparatusof claim 19, wherein the controller comprises a chamber adapted tocontain the bioactive agent.
 26. The apparatus of claim 19, furthercomprising a mechanical driver coupled near the proximal region, whereinthe mechanical driver retracts and extends the needle a controlled depthinto the cardiac tissue.
 27. An apparatus, comprising: a catheterconfigured for percutaneous insertion into a cardiac tissue, thecatheter having a proximal region, a steerable distal region, and alumen extending from the proximal region to the steerable distal region;a needle disposed distal to the steerable distal region and movablebetween a first position, wherein the needle is retracted within thedistal region, and a second position, wherein the needle is extendedbeyond the distal region; and a controller coupled near the proximalregion and having a source of a bioactive agent, wherein the controllerpasses a predetermined amount of the bioactive agent through the lumen,in fluid communication with the needle, for delivery into the cardiactissue, wherein the needle further comprises a means for depositing thepredetermined amount of the bioactive agent into the cardiac tissue, andwherein the catheter has a plurality of lumens, one of which containsthe bioactive agent and wherein the catheter has a conductor extendingfrom a proximal end of the catheter to an electrode which is distal tothe steerable distal region.
 28. The apparatus of claim 27, wherein thebioactive agent has a pellet form.
 29. The apparatus of claim 27,wherein the bioactive agent has a fluid form.
 30. The apparatus of claim27, wherein the controller mechanically measures a controlled amount ofthe bioactive agent.
 31. The apparatus of claim 27, wherein the needlefurther comprises an electrode adapted to delivery RF energy to thecardiac tissue.
 32. The apparatus of claim 27, further comprising amechanical driver coupled near the proximal region, wherein themechanical driver retracts and extends the needle a controlled depthinto the cardiac tissue.
 33. A method for delivering a bioactive agentto a patient's cardiac tissue, the method comprising: providing acatheter adapted for percutaneous insertion into the cardiac tissue, thecatheter having a steerable end region and a hollow needle adapted todeliver discrete units of a bioactive agent having a predetermineddosage and a push rod to push the discrete units, wherein the catheterhas a plurality of lumens, one of which contains the bioactive agent,wherein the catheter has a conductor extending from the proximal end ofthe catheter to the distal end of the catheter and the conductor iscoupled to an electrode which is distal to the steerable end region;inserting the catheter within the cardiac tissue; steering the steerableend region to dispose the hollow needle at a selected orientationrelative to an interior surface of the cardiac tissue; and deliveringand mechanically measuring a controlled amount of the bioactive agent tothe cardiac tissue.
 34. The method of claim 33, further comprisingdelivering a plurality of discrete units of the bioactive agent to thecardiac tissue.
 35. The method of claim 33 wherein delivering comprisesinjecting the bioactive agent under pressure sufficient to form a pocketof the bioactive agent in the cardiac tissue.
 36. The method of claim 33wherein delivering comprises injecting the bioactive agent in a pelletform.
 37. The method of claim 33 wherein delivering comprises injectingthe bioactive agent in a fluid form.
 38. The method of claim 33, furthercomprising delivering RF energy to the cardiac tissue.
 39. The method ofclaim 33, further comprising mechanically retracting and extending theneedle a controlled depth into the cardiac tissue.
 40. A method fordelivering a bioactive agent to a patient's cardiac tissue, the methodcomprising: providing a catheter adapted for percutaneous insertion intothe cardiac tissue, the catheter having a steerable end region and aneedle adapted to deliver discrete units of a bioactive agent having apredetermined dosage, wherein the catheter has a plurality of lumens,one of which contains the discrete units, and a push rod to push thediscrete units, wherein the catheter has a conductor extending from theproximal end of the catheter to the distal end of the catheter and theconductor is coupled to an electrode coupled to the needle near thesteerable end region; inserting the catheter within the cardiac tissue;steering the steerable end region to dispose the needle at a selectedorientation relative to an interior surface of the cardiac tissue; andmechanically delivering the predetermined dosage of the bioactive agentthrough the needle into the cardiac tissue using the push rod.
 41. Themethod of claim 40, further comprising delivering a plurality ofdiscrete units of the bioactive agent to the treatment site.
 42. Themethod of claim 41, further comprising mechanically measuring acontrolled amount of the bioactive agent.
 43. The method of claim 41wherein delivering comprises injecting the bioactive agent underpressure sufficient to form a pocket of the bioactive agent in thecardiac tissue.
 44. The method of claim 41 wherein delivering comprisesinjecting the bioactive agent in a pellet form.
 45. The method of claim41 wherein delivering comprises injecting the bioactive agent in a fluidform.
 46. The method of claim 41, further comprising delivering RFenergy to the cardiac tissue.
 47. The method of claim 40, furthercomprising mechanically driving the needle to control a penetrationdepth of the needle into the cardiac tissue.
 48. An apparatus fordelivering a bioactive agent to a patient's cardiac tissue, theapparatus comprising: means for providing a catheter adapted forpercutaneous insertion into the cardiac tissue, the catheter having asteerable end region and a hollow needle adapted to deliver discreteunits of a bioactive agent having a predetermined dosage, wherein thecatheter has a plurality of lumens, one of which contains the discreteunits, and a push rod to push the discrete units, wherein the catheterhas a conductor extending from the proximal end of the catheter to thedistal end of the catheter and the conductor is coupled to an electrodewhich is distal to the steerable end region; means for inserting thecatheter within the cardiac tissue; means for steering the steerable endregion to dispose the hollow needle at a selected orientation relativeto an interior surface of the cardiac tissue; and means for deliveringand mechanically measuring a controlled amount of the bioactive agent.49. An apparatus for delivering a bioactive agent to a patient's cardiactissue, the apparatus comprising: means for providing a catheter adaptedfor percutaneous insertion into the cardiac tissue, the catheter havinga steerable end region and a needle adapted to deliver discrete units ofa bioactive agent having a predetermined dosage, wherein the catheterhas a plurality of lumens, one of which contains the discrete units, anda push rod to push the discrete units, wherein the catheter has aconductor extending from the proximal end of the catheter to the distalend of the catheter and the conductor is coupled to an electrode whichis distal to the steerable end region; means for inserting the catheterwithin the cardiac tissue; means for steering the steerable end regionto dispose the needle at a selected orientation relative to an interiorsurface of the cardiac tissue; and means for mechanically delivering thepredetermined dosage of the bioactive agent through the needle into thecardiac tissue.
 50. An apparatus, comprising: a catheter configured forpercutaneous insertion into a cardiac tissue, the catheter having aproximal region, a steerable distal region which is deflectable, and alumen extending from the proximal region to the steerable distal region;a needle disposed distal to the steerable distal region and movablebetween a first position, wherein the needle is retracted within thedistal region, and a second position, wherein the needle is extendedbeyond the distal region and wherein the needle is deflectable withinthe steerable distal region; and a controller coupled near the proximalregion and having a source of a bioactive agent in the form of discreteunits, wherein the controller passes a predetermined amount of thebioactive agent through the lumen, in fluid communication with theneedle, for delivery into the cardiac tissue, wherein the needle furthercomprises a means for depositing the predetermined amount of thebioactive agent into the cardiac tissue, and wherein the catheter has aplurality of lumens, one of which contains the bioactive agent andwherein the catheter has a conductor extending from a proximal end ofthe catheter to an electrode which is distal to the steerable distalregion.
 51. The apparatus of claim 50, wherein the bioactive agent has apellet form.
 52. A method for delivering a bioactive agent to apatient's cardiac tissue, the method comprising: providing a catheteradapted for percutaneous insertion into the cardiac tissue, the catheterhaving a steerable end region and a hollow needle adapted to delivergranules of a bioactive agent having a predetermined dosage, wherein thecatheter has a plurality of lumens, one of which contains the granules,and a push rod to push the granules, wherein the catheter has aplurality of lumens, one of which contains the bioactive agent, whereinthe catheter has a conductor extending from the proximal end of thecatheter to the distal end of the catheter and the conductor is coupledto an electrode which is distal to the steerable end region; insertingthe catheter within the cardiac tissue; steering the steerable endregion to dispose the hollow needle at a selected orientation relativeto an interior surface of the cardiac tissue; and mechanicallydelivering a controlled amount of the granules using the push rod. 53.The method of claim 52, wherein the catheter includes a plurality ofgranules.
 54. The method of claim 53, wherein mechanically deliveringcomprises separating a single granule from the plurality of granules.55. The method of claim 54 additionally comprising inserting a singlegranule within the cardiac tissue.
 56. The method of claim 52additionally comprising inserting at least one granule into the cardiactissue and wherein the mechanically delivering comprises measuring thecontrolled amount.
 57. The method of claim 52, wherein insertingcomprises inserting the hollow needle into the cardiac tissue.
 58. Themethod of claim 57, wherein a portion of the catheter allows only thehollow needle to insert into the cardiac tissue.
 59. The method of claim57, wherein a path into the cardiac tissue is created by inserting thehollow needle.
 60. The method of claim 59, wherein the pathsubstantially closes after the hollow needle is withdrawn from thecardiac tissue such that the granule is in complete contact with thecardiac tissue.